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Title: Oxford University Behaviour and Genes notes first year Biomedical Sciences - lectures by Dorothy Bishop
Description: Thorough set of notes made from lectures given by Dorothy Bishop who carried out many well known genetic-behaviour experiments.
Description: Thorough set of notes made from lectures given by Dorothy Bishop who carried out many well known genetic-behaviour experiments.
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Genes and behaviour
Gain and Loss of a chromosome
Neurological disorder that result:
§ Down syndrome –C21 trisomy – 1/830 births
§ Turner syndrome
§ Sex chromosome trisomies
Mutation = small change in DNA sequence
Translocation = part on one chromosome attached to another
CNV (Copy number variation) = loss/gain of part of chromosome
Aneuploidy = duplication/loss of whole chromosome
All chromosomes are paired except for the Sex chromosomes
...
Down syndrome
Physiologically:
• Caused by duplication of C21
• Effects motor output and skills, particularly fine and gross motor skills due disproportionatly small
cerebellum
• By 40 neurofibilary tangles and plaques like in alzehiemrs present
• Suspectible to degeneration early in life such as hearing loss and cardiac problems
Behaviourally: LOTS OF VARIATION
• IQ impaired mild to severe
• Normal development neurologically until 2 years
• Language and memory is poor however could language difficulty be a secondary symptom which
arises as a result of hearing problems rather than directly from the genetic defect?
Down syndrome short term memory study: Jarrold and Baddeley 1997
Aim:
§ to understand the possible explanations for poor verbal short term memory in DS patients – does any
observed deficit actually reflect an underlying diffuclty in memory or is it caused by other factors?
§ Short term memory = ability to hold information
Method:
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Verbal using digit span – presented with series of numbers and asked to repeat back
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§
Does not prove DS have specific verbal shor term memory problem
§
May be little to do with memory such as hearing difficulties as digit span involves auditory
presentation – use headphones to eliminate possibility?
§
Problems with spoken articulation
§
However, there is relatively little evidence to for this suggestion after a series of follow up
experiments carried out to eliminate these factors
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Aim: understand if the origin of the behavioural symptoms displayed in DS is due to deficits in
mitotic pathways in the cerebellum
o Method:
§ sonic the hedgehog agonist which regulates mitotic pathway shortly after birth to promote
cellular growth in the cerebellum given to Ts65Dn mice and control genetic mice
§ measured motor output using morris water maze which has a hidden platform water made
opaque adding milk
§ learning is evaluated using the time taken to find the platform
o Results
§ Both control and Ts65Dn mice found platform when it was not hidden
§ Ts65Dn mice struggled when hidden as use if visuospatial cues outside tank required
§ Performance equivalent to controls when given sonic hedgehog agonist
§ Rescued MNDA receptor dependent synaptic plascitiy
o Interpretation
§ Ts65Dn mice have a deficit in visuospatial memory rather than motor skills generally
§ Confirm role of sonic hedgehog pathway in cerebellum development and direct influence in
hippocampacal function
§ Potential therapeutic technique
o Evaluation
§ No consistent cerebellum specific functional effect has been documented in Ts65Dn mice
§ SAG only recuses the number of granule cells and not their function – they have short Aps
and increased excitability
§ Better if registered earlier prenatal period
§ SAG may me impacting LTD in hippocampus to improve spatial; navigation
Treatments:
§ mitotic pathway -‐ sonic hedgehog agonists to promote cell growth
o Limitation –
§ cell growth promoter leading to cancer
§ SAG involved in development of neural crest and axis formation therefore difficult to apply
prenatally
...
Experiment using spontaneous alternation:
§ Assesses short term memory also
Method:
§ Mice allowed to explore T or Y shaped maze
§ Innate tendency of rodents to explore novel objects investigated by measuring the percentage of times
that the mouse chooses to visit a different arm than one it recently visited
...
o Incomplete activation as pseudoautosomal region at end of X and Y chromosomes not
inactivated and nor are 20% of the genes outside the pseudoautosomal region – these acts are
autosomal genes
o Randomly effects each chromosome of each pair
o Seen in cats which have different colour patches of fur due to different fur colour genes on the X
chromosomes and are inactivated relatively early on in development
...
Method:
§ Devise a TS phenotype score (TSCS score); mostly cognitive eg impaired viso-‐spatial abilities
§ Techniques used = X inactivation studies, microsateliite marker genotyping
§ Relate this score to how much of the inactivated X chromosome genes are missing
Results
§ People on left despite having little missing displayed same symptoms as TS
§ Those with a lot missing still were relatively normal
§ Mapping suggests that haploinsufficiency of one or more genes in inactivated X responsible for
neurocognitive phenotype
XXX – X trisomy
§ Only one X chromosome is fully active, however despite the extra X one being inactivated there are the
pseudoautosomal regions on the end and 20% outside of these which are still active therefore still extra
genetic material
XXY – Klinefelters syndrome
§ Extra X chromosome inactivated but still additional material from pseudoautosomal ends
...
5% had XYY which is higher than expected population prevelance of 0
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§ No link to violent acts, mostly crimes to do with property
Witkin et al 1976
Aim: role of extra Y and X chromsones in criminality of XYY and XXY men
Method:
§ In Denmark men are required to report to draft board for physical examination
§ Top 15% height men chosen
§ Genetic samples taken at homes and information about criminality and education taken from records
Results:
§ 12 XYY and 16 XXY men
§ Mean for these men was 1 SD below the mean
§ Crimes were not violent
Interpretation:
§ Simply more likely to be caught as lower IQ – not necessarily aggressive
Prenatal screening and unbiased samples could be carried out now with current technology but unethical
...
Extra X chromosome is more common and often goes unidentified
Do trisomies impact language impairments and autism?
Bishiop et al 2011
Aim: is variation due to nurture in the home and is autism linked to XXY klinefelter syndrome?
Method:
§ Two groups of parents with children with sex triosomies identified:
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Identified after therefore ascertainment bias
§ Both groups compared with sibling of same age as a control
Results:
§ Trisomy children greater language and communication educational difficulties than siblings
§ Autistic rate is substantially above population levels in this sample
Discussion:
§ The risk of autism may be increased in those with XXY genotype but the majority of those who are
autistic are not XXY
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§ Could be relating to parental age – older parents are more likely have prenatal screening due a greater
risk of child disabilities
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Why is there variation within the same syndrome?
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Aetiology is complex and multifactorial in these syndromes
§ Relatively common disorders which cause infertility yet still persistant in the population
§ Disorders aggregate but do not segregate in families
§ Unaffected relatives of affected indivduals may show mild symptons
§ High heritability in twin studies yet genome scans show reveal very few single gene causes
§ Genetic background autosomes which may interact with the trisomer and supress them
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Maternal or paternal X chromosome can effect genetic imprinting and the random pattern of inactivation in
each
Impact of genetic mutation on behaviour lecture 2
Mutation – very rare
Polymorphism – found more commonly (>1%) – only difference in definition is frequency
Types of mutations:
§ Silent – same amino acid
§ Missense – different amino acid
§ Nonsense – stop codon
Specific language impairement:
§ When language does not follow normal developmental course and not due to hearing loss, physical
abnormality or brain damage
§ Normal development and other areas
§ Difficult to pin down cause as multiple different variations of condition
Causes:
• Seen that language difficulty rates higher in relatives of those with SLI compared to the controls
• Family aggregation as opposed to segregation suggesting that it is a multifactorial defect and not
necessarily caused by a single disease
• Does not prove it is genetic as it can be due to common environment eg diet
...
Three methods of research of FoxP2 involvement in language:
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Phenotype refinement – in humans refining phenotype to include neural structure and functional
correlations
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Evolution
§ Suprisingly FoxP2 is very highly conserved with only 3 AA positions differing in rat and human FoxP2 –
suggesting that it is not simply the ‘language/speech’ gene as our language is significantly more complex
than that of the rat
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§ Important to understand it would not have been the only gene to undergo changes and positive
selection in human history
§ Rather than its selection being major force for speech development it is more so within a framework of
other events integrated together
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§ Remains unclear whether these deficits are confined to oromotor system or represent a more general
impairment of motor control which impacts primarily on speech due to the intense demands of human
spoken language
...
§ Or a procedural learning deficit? Learning of sounds and words is involved in sequential unconscious
learning?
§ Pleiotropic effect – mutation may have multiple parallel effects on distinct aspects of brain development and
therefore multiple neural circuits so a range of potential scenerios may account for the relationship that is
scene between language development and oromotor skills
§ Procedural learning -‐ May simply be a secondary result of impaired speech articulation in early development
due to basic motor control defect?
Method of tracking down location of genes: LINKAGE ANALYSIS in KE family; Lai et all 2000
Aim: A pedigree based approach to gene mapping to find markers which are close to the hypothetical gene locus
...
Method:
§ First recruit families known to have individuals with SLI
§ Non-‐coding junk DNA used as a genetic marker as significant variation enough that one can work out
from which parent and on which chromosome the gene is present -‐ polymorphic markers
§ Existence of recombination allows one to map potential risk genes to specific chromosomal locations
...
§ Analyse common genetic factors between affected parents and children with similar SLI phenotype
Results:
-‐ Observed exchange of material on chromosomes 5 and 7
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Similar as they use vocalisation that are imitatively
learnt during a critical period
§ influenced by the environment and social factors
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Humans: human basal ganglia
§ DLM – part of feedback loop enabling comparioson of own song template – human
dorsolateral medial thalamus
o Gene manipulation in Area X:
§ Inject zebra finches with tailored piece of RNA which inhibits the FoxP2 gene
§ Song control brain circuits have already developed
§ Result: birds don’t learn new songs or repeat known songs properly with syllabus left out or
wrong pitch or sung incorrectly
§ Conclusion: dichotomous role of FoxP2:
o Involved in formation of circuitry employed for sensory guided motor learning by influencing
neuronal differention
o Needed for proper functioning of these circuits in learning juveniles and to switch singing style in
adults
Mouse studies:
§ Mice produce social vocalisations
§ Deaf mice also vocalise showing it is not simply something they do to be able to hear themselves
Aim Castellucci 2016: The effect of knocking out Foxp2 in mice on their vocalisations:
Method:
-‐ Knock out homozygous foxp2
-‐ Knowck out heterozygous foxp2
Results:
-‐ Mouse vocalisations consist of bouts of calls separated into syllables by periods of silence
-‐ homozygous knock out results in stark abnormalities in pup and isolation calls and eventually death from
early motor and respiratory defects
-‐ Heterozygous KO – little impact on pup vocalisation but has a big impact on courtship vocalisation produced
longer syllabules and defects in temporal aspects of song
Interpretation:
-‐ Shows foxp2 is necessary for normal vocal behaviour in juvenile and adult mice
-‐ Humans with FOXP2 mutations also shown to have strong speech timing abnormalities and rhythmic
distortions were seen in the rats – possibly to do with common motor deficit not specific to language?
-‐ Therefore, further study of Foxp2 mutant mice and their vocalizations may provide valuable insights into the
role of these brain regions in generating the coordinated rhythmic orofacial motor behavior that is essential
for human speech production
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Results:
-‐ Slower learning in missense mutation similar to KE family
-‐ Very poor learning in the nonsense mutation mice
Discussion:
-‐ This study is moving away from speech and language parallel of motor learning
-‐ One study on its own is simply not compelling and hearing a sound and jumping is not a good model for
measuring learning ability as so many other factors such as motor skills and development contribute to the ability
to jump
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Evidence of both mouse and human playing roles in neural
circuitry from examination of expression patterns
§ Foxp2 is found in other organs such as lungs and plays a role in their development – must view FOXP2 in
the context of systems biology recruited for repeated use in different pathways
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FOXP2:
§ Hyped by media as the language gene
§ Genetic mutation of gene thought to affect speech and language
§ Huge debate over function of gene
§ More so one critical piece of a complex puzzle
Conclusion about FOXP2:
-‐ New questions that are arising which are most exciting
-‐ Several levels of approach being used to look at it from a molecular level all the way up to a behaviour level
by seeing its effects on neuronal cells in culture and interfrating findings with neuroimaging data
-‐ Likely other genes will be discovered which also play a significant role in speech
-‐ Shows how molecular genetics is capable of bridging several disciplines
Complex multifactorial aetiology lecture 3
§ These aggregate but do not segregate in families meaning it runs through families but cannot trace the
effect of the gene
§ Different to simple Mendelian hereditary pattern as if it were caused by a single gene it would have been
selected out of the population
o Heart disease
o Diabetes
o Dyslexia
o ADHD
o SPI
Dyslexia:
Symptoms
-‐ Unexpected difficulty to read which is not explained by a
o lack of opportunity to learn
o hearing problem
o brain damage
-‐ Usually a linguistic problem rater than a visual difficulty
Defining dyslexia is difficult and therefore the number of people who have been catergorized as having dyslexia has
changed as it depends on:
-‐ Reading ability cut off
-‐ IQ inclusion or not
-‐ Type of reading test used – ability to understand or read out loud?
-‐ What exclusionary factors are used
Methods for identifying genetic influences on multifactorial disorders:
By identifying the genetic differences it would enable one to distinguish between a dyslexic and a poor reader
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Molecular genetics: identifying DNA variants associated with phenotypes
Twin study methods:
MZ – genetically identical and always same sex
DZ – share 50% of the same alleles for polymorphic genes and same sex is used so no sex gene differences
interfering
-‐ Phenotype can be effected by both genes and the environment; twin studies can help us to understand this
-‐ Shared environment is confounded with genetic effects thus we need to untangle this
General method for twin studies:
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5 and MZ 0
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if there was no genetic influence and it was simply by random chance with no common shared environment
there would be 0 correlation
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Only shared environment determinant = 1 for both MZ and DZ
Genes and shared environment gives a positive correlation
Difference in environment give negative correlation between twins
Reading scores – Harlaar 2005
Aim: to obtain an estimate for the proportion of the variance of the trait that is genetic (heritability) by using
correlation between twins which is the equivalent of the sum of the shared environmental and genetic factors thus
suggesting the origins of the individual differences in reading at an early age
Method:
-‐ Word recognition measured
-‐ Analyses allowing for sex differences in aetiology used to estimate the extent to which genetic and
environmental factors contribute to variation in in word recognition and difficulties in this
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85
-‐ HZ twins = 0
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-‐ Take observed data and test assumptions and add measures of the environment and confidence intervals
-‐ Approach allows more flexibility therefore modelling of multivariate data to examine genetic and
environmental relation between 2+ phenotypes
Heritability
§ A population statistic-‐ does not make it untreatable or a fixed property of an individual or phenotype
§ Merely indicates what proportion of genetics relates to heritability eg herability in finland for education is
high as the main factor for failing would be biological as good education whereas genetics is not a high
proportion in Brazil therefore the heritability is low
§ Environmental contribution to the varience only refers to the current environmental condition: new
environmental factors eg insulin for diabetes effect heritability
Molecular genetics approach
-‐ Typical approach in which genetic variants which are found to differ in the clinical and control groups are
identified
-‐ It is obvious to compare the DNA of someone with a condition with someone without it but the problem is
that there is too much DNA to compare!
-‐ Association analysis – classical way of investifating genetics: Newbury (2009) this tests how one repeats
nonsense words and found two genes on C16 are associated with a drop in nonword repition ability in a
language impaired sample
o 1
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Risk alleles only have a small effect -‐ neither would make you impaired in language like FOXP2
mutation which clearly results in an abnormal defect
o This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides
molecular evidence for the importance of phonological short-term memory in
language acquisition
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Doesn’t involve picking out bits of genetic material associated with trait
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instead compare allele frequencies of thousands of common variants between large samples of disease
cases and controls
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take all p values
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ALLOWS ALL GENES TO BE CONSIDERED RATHER THAN CHERRY PICKING CANDIDATES
Comparing methods for calculating heritability: GWAS vs Twin studies
GWAS: found 54 SNPs related to height but the effects were small with them accounting for 5%
Twins Studies: estimated heritability for height was 80%
Major difference between twin studies and GWAS – estimates in behavioural measures also such as reading and IQ
also find that twin studies give high estimates whereas GWAS find only small effects
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o Gene to gene interaction between = greater difference in genotypes between DZ and MZ
twins as only DZ will show variation
o There will be a distortion in the genetic correlation in DZ but not MZ as they are genetically
identical
2) or the GWAS studies too low : fails to detect significant heribility
§ Only looks for association between phenotypes and genotypes and does not detect heriibility to gene-‐
enviornment and gene-‐gene interactions
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Heritable
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Inheritance of genetic liability is not sufficient to predict whether a person will develop the disease
Also described as polygenic which suggests that the disorder results from the combined effect of multiple genes:
It is described as this as it is observed to agreggrate but not segregate in families like in simple Mendelian
inheritance:
-‐ This is true for disorders in which risk of disease is increased if relative has a disease
This interpretation of disorders as polygenic is what gave rise to GWAS
This conclusion is based entirely on circular logic and a number of unfounded assumptions, particularly the
assumption that the disorder in question represents a single biologically valid category by lumping all cases
together and calculating heritability and relative risks across the entire population
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§ Non genetic factors may also be important: environmental and intrinsic developmental variation – hence
why not 100% concordance in MZ twim phenotypes
Genome wide complex trait analysis (GCTA)
-‐ Doesn’t look at individual sections of DNA but instead finds similarities between all DNA using all of the
SNPs to find index of relatedness
-‐ Comparision of SNPs to measure relatedness seen whether or not it maps onto phenotypic similarities
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-‐ Higher estimates of heritability but still less than twin studies
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DCDC2 is only a gene which has been associated with dyslexia, there is no causativity confirmed and only in a
few studies
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005
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Typical study =
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Compare brain structure of those with different genetic variants
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Title: Oxford University Behaviour and Genes notes first year Biomedical Sciences - lectures by Dorothy Bishop
Description: Thorough set of notes made from lectures given by Dorothy Bishop who carried out many well known genetic-behaviour experiments.
Description: Thorough set of notes made from lectures given by Dorothy Bishop who carried out many well known genetic-behaviour experiments.